Regulation of the ionic milieu of the extracellular space of the brain is important in seizures, but our understanding in this area is incomplete, especially in chronic epilepsy. Recent investigations suggest that the homeostasis of extracellular potassium ((K+)o) and calcium ((Ca++)o) is distributed in the chronically epileptic brain and that this type of tissue has a heightened sensitivity to the epileptogenic effects of displacing extracellular ionic concentrations away from their normal resting levels. Our laboratory has developed and characterized a number of interconnected models of limbic seizures which are centered in the hippocampus. The epileptic states associated with these models are rapidly produced but, once established, are long- lasting. This fact makes them particulary well-suited to study the homestasis of (K+)o and (Ca++)o in various epileptic conditions. In this project, complementary in vivo and in vitro studies will be carried out to address the role of (K+)o and (Ca++)o in chronic epilepsy and status epilepticus. The use of ion-sensitive microelectrodes in vivo will be combined with manipulations of the ambient, resting (K+)o and (Ca++)o in hippocampal slices to test 4 hypotheses. Hypothesis 1 states that an elevated (K+)o and/or decreased (Ca++)o is causative for the initiation of seizures in the hippocampus. Hypothesis 2 states that (K+)o and (Ca++)o homeostasis is disturbed in chronic hippocampal epilepsy and in the hippocampus exhibiting status epilepticus. Hypothesis 3 states that chronically epileptic tissue has an increased sensitivity to the epileptogenic effects of elevated (K+)o and/or decreased (Ca++)o. Hypothesis 4 states that the ambient (K+)o and (Ca++)o influence the consequences of intense neuronal activation, determining whether responses are epileptic or not. The information from these experiments will elucidate basic mechanisms of epilepsy in order that we can better understand the cause and consequences of this disorder.